Drug delivery system

ABSTRACT

The subject invention provides a drug delivery system comprising at least one compartment consisting of (i) a drug-loaded thermoplastic polymer core, (ii) a drug-loaded thermoplastic polymer intermediate layer and (iii) a non-medicated thermoplastic polymer skin covering the intermediate layer, wherein said intermediate layer is loaded with (a) crystals of a first pharmaceutically active compound and with (b) a second pharmaceutically active compound in dissolved form and wherein said core is loaded with said second compound in dissolved form.

FIELD OF THE INVENTION

The present invention relates to the field of female contraception andhormone replacement therapy.

The present invention relates to a drug delivery system (device) for thesimultaneous release of two or more active substances and moreparticularly to a ring shaped vaginal drug delivery system, which systemreleases the active substances in a substantially constant ratio over aprolonged period of time. Since the invention pertains to a drugdelivery article for intra-vaginal use, its use is focussed on typicallyfemale medical indications, such as contraception andhormone-replacement The article according to the invention isparticularly in the form of a ring, and will hereinafter be referred toas a vaginal ring.

BACKGROUND OF THE INVENTION

Vaginal rings are known Background art in this respect includes thefollowing patent documents.

U.S. Pat. Nos. 3,995,633 and 3,995,634, describe separate, preferablyspherical or cylindrical, reservoirs containing different activesubstances which are assembled in specially constructed holders.

U.S. Pat. No. 4,237,885 describes a tube or coil of polymeric materialwhich is divided into portions by means of a plurality of “spacers”provided in the tube, after which each of the separate tube portions isfilled with a different active substance in a silicone fluid and the twoends of the tube are subsequently connected to one another. In thisrelease system, however, transport (diffusion) of active material fromone reservoir to the other takes place through the wall of the tube,especially upon prolonged storage, so that the pre-set fixed releaseratio between the active substances in question will change over aperiod of time.

European patent publication 0,050,867 discloses a two-layered vaginalring which comprises a pharmacologically acceptable supporting ringcovered by two layers preferably of silicone elastomers whereby theinner layer is a silicone elastomer loaded with an active substance.

U.S. Pat. No. 4,292,965 describes a ring shaped vaginal delivery systemof three layers made of silicone elastomers.

U.S. Pat. No. 4,596,576 describes a two-compartment vaginal ring whereineach compartment contains a different active substance. To achieve asuitable ring with a constant release ratio between the various activesubstances, the end portions of the compartments are joined by glassstoppers.

Patent Publication WO 97/02015 describes a two-compartments device, afirst compartment consisting of a core, a medicated middle layer and anon medicated outer layer, and a second compartment consisting of amedicated core and a non medicated outer layer.

EP 876 815 discloses a vaginal ring (Nuvaring®) which is designed forthe simultaneous release of a progestogenic steroid compound and anestrogenic steroid compound in a fixed physiological ratio over aprolonged period of time. The drug delivery system comprises onecompartment comprising a thermoplastic polymer core containing themixture of the progestogenic and estrogenic compounds and athermoplastic polymer skin, the progestogenic compound being initiallydissolved in the polymer core material in a relatively low degree ofsupersaturation.

From the above disclosures, it is clear that e.g. the material, thelayers and the compartments are all aspects of a ring device which playa role in the designs that have been developed

All choices are usually made with a view to obtain a constant releasepattern, which is complicated when two or more active substances areinvolved. The latter is of particular importance in the field ofcontraception, as for this purpose often a combination of a progestagenand an estrogen is used. Also in hormone replacement, however, it isdesired to have rings which deliver combinations of drugs.

Among the above disclosures, EP 876 815 clearly sets a standard; itinvolves a one-compartment design, it obviates the need for silasticpolymer by using EVA combinations, and it releases two or more activesubstances in a substantially constant ratio to one another over aprolonged period in time.

As any product of technology at all times however, also the latter canstill be improved upon. The drug delivery device disclosed in EP 876815is physically stable only when stored below room temperature. Itrequires storage and transport below room temperature which is expensiveand requires a lot of attention. Moreover, if not stored below roomtemperature, steroid eventually crystallizes out onto the skin of thedevice which may lead to uncontrollable and high burst release.

The subject improved drug delivery system solves this problem since itis physically stable under room temperature conditions and thus does notneed special storage and transportation conditions.

Moreover, in the subject improved drug delivery system, it is possibleto adjust the release rate of more than one pharmaceutically activecompound independently from one another, while maintaining the physicalstability of the system.

SUMMARY OF THE INVENTION

The subject invention provides a three-layer design vaginal ring,physically stable at room temperature, from which at least twopharmaceutically active compounds can be released independently from oneanother.

The ring comprises at least one compartment comprising (i) a medicatedthermoplastic polymer core, (ii) a medicated thermoplastic polymerintermediate layer and (iii) a non-medicated thermoplastic polymer skincovering the intermediate layer. The intermediate layer is medicated(loaded) with (a) crystals of a first active substance and with (b) asecond active substance in dissolved form. The core is loaded with thesecond active substance as welt optionally in the same concentration asin the intermediate layer.

FIGURES

FIG. 1:

In vitro release rates of etonogestrel (ENG) for all 4.0 mm batches.

FIG. 2:

In vitro release rates of etonogestrel for all 3.5 mm batches.

FIG. 3:

In vitro release rates of ethinyl estradiol (EE) for all 4.0 mm batches.

FIG. 4:

In vitro release rates of ethinyl estradiol for all 3.5 mm batches.

FIG. 5:

Schematic description of a vaginal ring of the subject invention.

FIG. 6:

In vitro-release rates of etonogestrel and ethinyl estradiol from one A1ring.

FIG. 7:

In vitro-release rates of etonogestrel and ethinyl estradiol from one A2ring.

FIG. 8:

In vitro-release rates of etonogestrel and ethinyl estradiol from one A3ring.

FIG. 9:

In vitro-release rates of etonogestrel and ethinyl estradiol from one A4ring.

FIG. 10:

In vitro-release rates of etonogestrel and ethinyl estradiol from one B1ring.

FIG. 11:

In vitro-release rates of etonogestrel and ethinyl estdiol from one B2ring.

FIG. 12:

In vitro release rates of etonogestrel and ethinyl estdiol from one B3ring.

FIG. 13:

In vitro-release rates of etonogestrel and ethinyl estradiol from one B4ring.

FIG. 14:

In vitro release rates of etonogestrel for fibre variants E, F, G, H andL

FIG. 15:

In vitro release rates of etonogestrel for fibre variants J, K, L, W andX.

FIG. 16:

In vitro release rates of etonogestrel for fibre variants M, N, O. P andQ.

FIG. 17:

In vitro release rates of etonogestrel for fibre variants R, S, T, U andV.

FIG. 18:

In vitro release rates of ethinyl estradiol for fibre variants E, F, G,H and I.

FIG. 19:

In vitro release rates of ethinyl estradiol for fibre variants J, K , L,W and X.

FIG. 20:

In vitro release rates of ethinyl estradiol for fibre variants M, N, O,P and Q.

FIG. 21:

In vitro release rates of ethinyl estdiol for fibre variants R, S, T, Uand V.

DETAILED DESCRIPTION OF THE INVENTION

Fick's law of diffusion governs the release of compounds, such ascontraceptive steroids from a ring. According to this law, the amount ofmass transferred over the boundary is an inverse function of thedistance across the boundary. In a two-layer design, the steroid nearestto the outer layer (the skin) will diffuse first and this results indepletion of the outer core and hence the diffusion distance willincrease. The depletion of the outer core layer and the resultingincrease of the diffusion distance will result in a decrease of therelease rate. When speaking about the release rate of one drugsubstance, the problem of depletion and increase of the diffusiondistance can be overcome by concentrating the drug substance in anintermediate layer between a placebo skin and a placebo core. Since thedrug substance is then concentrated in a relatively thin layer,lengthening of the diffusion distance during release is minimal,resulting in a more constant release rate over time.

The release rate of a cylindrical reservoir/membrane design is:dM=2πL D _(p) K _(p/s) ΔCdt Ln (r₀/r₁)

-   -   L=the length of the cylinder    -   D_(p)=the diffusion co-efficient of the compound in a skin        polymer    -   K_(p/s)=partition coefficient of the steroid between the skin        and core polymer    -   ΔC=the difference in concentration between the core (or        intermediate layer) and the sink    -   r₀=is the overall radius, i.e. the radius of the cylinder        including the skin    -   r₁=is the radius of the core

The equation shows that zero order release is obtained when the term onthe right hand side of the equation is constant, i.e. not a function oftime. Lengthening of the diffusion distance due to depletion of the coreis insignificant in a three-layer design containing one drug substanceand hence the term (r₀/r₁) may be considered almost constant. In casethe steroid in the intermediate layer is present in the dissolved state,the concentration gradient (ΔC) will steadily decrease in time andconsequently the release rate dM/dt will decrease (deviate from zeroorder release kinetics).

The subject invention provides a drug delivery system comprising atleast two active drug substances.

The subject invention provides a drug delivery system, typically asubstantially ring-shaped form intended for vaginal administration,which comprises at least one compartment consisting of (i) athermoplastic polymer core, (ii) a thermoplastic polymer intermediatelayer and (iii) a thermoplastic polymer skin covering the intermediatelayer, wherein said intermediate layer comprises (a) crystals of a firstpharmaceutically active compound and (b) a second pharmaceuticallyactive compound in dissolved state and wherein said core comprises saidsecond compound as well, optionally in the same concentration as in theintermediate layer.

The essence of this novel three-layered ring of the subject inventionlies in the provision of the possibility to adjust the release rates ofmore than one pharmaceutically active compound independently from eachother while maintaining the physical stability of the ring at roomtemperature.

This is accomplished by (1) incorporating crystalline reservoirs of the(first) compound in the intermediate layer of the ring, (2) loading boththe intermediate layer and the core of the ring with the second compoundin dissolved form, thereby enlarging the compound reservoir, and (3)defining the thickness of the skin of the ring.

In a specific embodiment of the subject invention, the compounds aresteroids. For the sake of ease, we hereinafter refer to steroids,although also non-steroidal compounds are contemplated by the subjectinvention as well.

The steroid molecules incorporated in the crystalline lattice are indynamic equilibrium with the steroid dissolved in the polymer of theintermediate layer. When no diffusion occurs, the steroid concentrationin the polymer will equal or come close to the equilibriumconcentration. After the ring has been put in a sink, steroid will startto diffuse out of the ring and the concentration of the steroiddissolved in the polymeric intermediate layer will drop slightly. As aconsequence thereof, the steroid crystals will start to dissolve. Thus,the decrease of the concentration gradient due to diffusive transportout of the ring is counterbalanced by the steroid in the crystallinereservoir. FIGS. 1 and 2 illustrate this stabilizing effect of crystalsin the intermediate layer. In the beginning, the slope of the releasecurve is very flat, i.e. indicates that the release is almost zero orderup to day 10. Then, after day 10, the release curve suddenly becomesmuch steeper, i.e. the release rate becomes more time dependent (lesszero order). Apparently this moment coincides with the moment that thesize and amount of crystals in the polymer matrix has decreased beyond acertain point and from this point on the loss of steroid due todiffusion outside the ring can no longer be adequately counterbalancedby crystals going into dissolution. When the majority of crystals aredissolved the concentration gradient is no longer stabilized and hence asteeper curve is seen. The stabilization of the concentration gradientby this mechanism functions when the dissolving of the steroid crystalsproceeds fast compared to the loss of steroid due to diffusion. So, theconcentration drop is counter balanced to a certain extent, and the neteffect will be zero provided the crystals dissolve relatively fast inthe polymer.

In other words, the subject three-layer design is a three-layered ringcomprising at least one compartment consisting of (i) an intermediatelayer loaded with two steroids, one (steroid A) partly present in thecrystalline phase and partly dissolved in the polymer and the other(steroid B) entirely dissolved in the polymer, (ii) a core loaded withsteroid B (entirely dissolved and optionally in the same concentrationas in the intermediate layer) and (iii) a placebo skin.

In the subject three-layered ring, steroid B is not only accommodated inthe intermediate layer, but also in the core. In one embodiment of thesubject invention, the concentration of steroid B is the same in thecore and in the intermediate layer.

By loading both core and intermediate layer with steroid B, thereservoir for steroid B is largely increased, allowing a fairly constantrelease rate of this steroid over a prolonged period (see FIGS. 3 and4). As a result of this design, the release rate of steroid A and therelease rate of steroid B can be adjusted independently from each other.Moreover, by loading the core with steroid B, also back-diffusion ofsteroid B from the intermediate layer back to the core is preventedBack-diffusion of steroid B would lead to a steadily decreasingconcentration in the intermediate layer and thus a decreasing releaseprofile upon storage (until even distribution of steroid B in core andintermediate layer). Also steroid. A may backuse into the core. This ishowever less critical since the concentration of steroid A in theintermediate layer is stabilized because of its presence in crystallineform In a special embodiment of the subject invention, steroid A, indissolved form, can however also be loaded into the core. This willreduce (or eliminate) internal diffusion effects.

Thus, the concept of this three-layer vaginal ring is to concentratesteroid in a relatively thin intermediate layer wherein part thereofwill be present in the form of crystals dispersed in the thinintermediate layer. The desired release rate of steroid A is obtained byadjusting the skin thickness. Therefore, steroid A is incorporated incrystalline form and steroid B in dissolved form thereby making itpossible to adjust the concentration of steroid B to the already pre-setskin thickness. Since the volume of the intermediate layer may berelatively small, this approach may lead to a relatively small contentand may become depleted relatively fat A possible too fast depletion ofthe three-layered ring is prevented by loading the core with the secondsteroid (B) as well.

In a different embodiment of the subject invention, the drug deliverysystem is a three-layered vaginal ring comprising at least onecompartment consisting of (i) an intermediate layer loaded with steroidA partly present in the crystalline phase and partly dissolved in thepolymer and (ii) a core loaded with steroid B which is entirelydissolved in the polymer and (iii) a placebo skin. This ring design,although containing only one steroid in the intermediate layer (asopposed to two steroids in the ring design described above), will, aftersome time, turn into the same design as the ring described above whereinthere are two steroids in the intermediate layer. This is because over aperiod of time, steroid B will diffuse into the intermediate layer andat a particular point in time will contain (i) an intermediate layermedicated with two steroids, one (steroid A) partly present in thecrystalline phase and partly dissolved in the polymer and the other(steroid B) entirely dissolved in the polymer, (ii) a core loaded withsteroid B (entirely dissolved) and (iii) a placebo skin.

The vaginal ring of the subject invention can be manufacture by theknown process of extrusion, such as co-extrusion and/or blend-extrusion.The drug-loaded core, the drug-loaded intermediate layer and thenon-medicated outer layer are all co-extruded. The fibres thus obtainedare cut into pieces of the required length and each piece is assembledto a ring-shaped device in any suitable manner. The rings are thenpacked for example in a suitable sachet, optionally after beingsterilized or disinfected.

The thermoplastic polymer that can be used in practising the invention,may in principle be any thermoplastic polymer or elastomer materialsuitable for pharmaceutical use, such as low density polyethylene,ethylene-vinylacetate copolymers and styrene-buladiene-styrenecopolymers. In a specific embodiment, ethylene-vinylacetate copolymer(poly-EVA) is used due to its excellent mechanical and physicalproperties (e.g. solubility of the steroids in the material). Thepoly-EVA material may be used for the core, the intermediate layer aswell as the skin and can be any commercially availableethylene-vinylacetate copolymer, such as the products available underthe trade names: Elvax, Evatane, Lupolen, Movriton, Ultrathene, Atevaand Vestypar.

In one embodiment both core and intermediate layer are made out of thesame polymer grade. In another embodiment, the core and the intermediatelayer are not made out of the same polymer grade in order to allow forFaber flexibility of the ring. By electing different polymer grades forthe core and the intermediate layer, fine-tuning of the flexibility ofthe ring is possible.

The vaginal ring according to the invention can be manufactured in anysize as required. In one embodiment, the ring has an outer diameter(outer circumference) of between 50 and 60 mm and in another embodimentbetween 52 and 56 mm; the cross sectional diameter is between about 2.5and 5 mm, in a specific embodiment between about 3.0 and 4.5 mm, and inanother embodiment between about 3.5 and 4.0 mm and in yet anotherembodiment is 4.0 mm.

It is also an object of the subject invention to provide an improvedvaginal ring in which the intermediate layer and/or the core, inaddition to steroids for contraception or hormone replacement, alsocomprises anti-microbials, e.g. to concomitantly treat and/or preventsexually-transmitted diseases (STD's) such as HIV, herpes, chlamydia andgonorrhoea.

In the subject invention, the surface of the core body is more than 800m², and in another embodiment more than 1000 mm² and will typically bein the order of 1700-2200 m², though significantly larger surfaces arepossible, provided that the design (physical dimensions) of the vaginalring prevents inconvenience for the subject It may sometimes be requiredto add a second compartment which is a placebo compartment or acompartment loaded with one or more other drugs. Such an extracompartment may be necessary for example in practising hormonalreplacement therapy, where the ratio between proestrogen and estrogen isdifferent from the ratio suitable for contraception. Such an extracompartment can also be necessary to administer, in addition to thesteroids, anti-microbial drugs to treat and/or prevent STD's such asAIDS, chlamydia, herpes and gonorrhoea.

Any anti-microbial drug can be incorporated into a vaginal ring of thesubject invention (in the intermediate layer and/or in the core and/orin an additional compartment). The anti-microbial drug can be anyanti-bacterial drug such as any antibiotic, any anti-viral agent, anyanti-fungal agent or any anti-protozoal agent An example of ananti-microbial drug contemplated to be incorporated into the vaginalring of the subject invention is mandelic acid condensation polymer(Zanefeld et al. (2002), Fertility and Sterility 78(5): 1107-1115).Another example is dapivirine(4-[[4-[2,4,6-trimethylphenyl)amino-2-pyrimidinyllamino]benzonitrile).

FIG. 5 shows a schematic description of the vaginal ring of the subjectinvention. R₁ is the diameter of the three-layered fibre. R₂ is theradius of the core together with the intermediate layer and R₃ is theradius of the core. The ratios of R₁/R₂ and R₂/R₃ described in thatfigure are defined as follows: Ranges R₁/R₂ R₂/R₃ Embodiment 11.0075-2.0000 1.0075-2.0000 Embodiment 2 1.0100-1.5000 1.0200-1.5000Embodiment 3 1.0300-1.3000 1.0200-1.5000 Embodiment 4 1.0400-1.18001.0200-1.0500 Embodiment 5 1.0300-1.2000 1.0100-1.0900

As used herein, “room temperature” lies anywhere between about 18° C.and about 30° C.

As used herein, a physically stable drug delivery system (ring) is asystem which can be stored at about 18° C.-30° C. for at least about oneand a half (1.5) year without steroid crystal formation on the surfaceof the skin of the vaginal ring.

The vaginal ring according to the invention is primarily designed forcontraceptive use, but—as said above—may also be used under certainconditions in HRT (hormonal replacement therapy).

The vaginal ring of the subject invention may—as said above—also be usedto concomitantly provide contraception and combat microbial disease. Themicrobial infection to be treated and/or prevented can be any bacterial,viral fungal or protozoal infection. Specifically, sexually transmitteddiseases such as HIV, chlamydia, gonorrhoea, or herpes may be treated byincorporation of an anti-microbial agent into the ring of the subjectinvention.

It is a further object of the invention to provide a method ofcontraception which comprises the steps of positioning a drug deliverysystem of the subject invention within the female vaginal tract andretaining the system within the vaginal tract for at least approximately21 days.

It is another object of the subject invention to provide a method ofconcomitantly providing contraception and treating or preventing asexually transmitted disease which comprises the steps of positioning adrug delivery system of the subject invention within the female vaginaltart and retaining the system within the vaginal tract for at leastapproximately 21 days.

In one embodiment, the drug delivery system is removed after about 21days for an approximate one week period to permit menstruation. In otherembodiments, the drug delivery system is removed after about 42, 63, 84,105, 126, 147, 186, 189, 210, 231, 252, 273, 294, 315, 336 or 357 daysfor an approximate one week period to permit menstruation. After theapproximate week to allow for menstruation, a new drug delivery systemof the subject invention is inserted into the female vagina to providecontraception in the next female cyclus or cyclusses.

The subject invention further envisions a use of a drug delivery systemof the subject invention for the manufacture of a contraceptive kit.

The subject invention further encompasses a use of a drug deliverysystem of the subject invention for the manufacture of a medicament forhormone replacement therapy.

The subject invention also provides a use of a drug delivery system ofthe subject invention for the manufacture of a combination preparationto provide contraception and to treat and/or prevent a sexuallytransmitted disease such as for example AIDS, herpes, chlamydia andgonorrhoea.

The progestogenic steroidal compound of the subject invention can be anysuitable proestrogen, such as desogestrel, etonogestrel, levonorgestrel,norgestimate, gestodene or any other steroidal compound withprogestogenic activity. The estrogenic steroidal compound can be anysuitable estrogen, such as estradiol, estdiol, mestranol andethinyl-estradiol. In a specific embodiment of the subject invention,the proestrogen is etonogestrel. In a specific embodiment of the subjectinvention the estrogen for contraceptive use is ethinylestradiol. Inanother embodiment, estradiol is the estrogen used for HRT.

In one embodiment of the subject invention, ethinyl estradiol is presentin the intermediate layer and in the core at about 0.05-1.5% by weightIn other embodiments, ethinyl estradiol is present in the intermediatelayer and in the core at about 0.08-0.5% by weight, at about 0.09-0.20%by weight, at about 0.09-0.18% by weight or at about 0.09-0.15% byweight.

In one embodiment of the subject invention, etonogestrel is present inthe intermediate layer at about 6-80% by weight. In other embodiments,etonogestrel is present in the intermediate layer at about 6-70% byweight, at about 10-53% by weight, at about 10-30% by weight, at about10-15% by weight, or at about 10-12% by weight

The subject invention also provides a method of manuf cturing thethree-layered drug delivery system of the subject invention by:

-   -   (i) Producing a loaded (medicated) homogenous polymer core        granulate and a loaded (medicated) homogeneous polymer        intermediate layer granulate;    -   (ii) Co-extruding the core granulate and the intermediate layer        granulate with a polymer skin granulate to form the        three-layered drug delivery system.

The production of the loaded (medicated) homogeneous polymer coregranulate and loaded (medicated) homogeneous polymer intermediate layergranulate comprises:

-   -   (a) grounding the polymer,    -   (b) dry powder mixing the grounded polymer with the active        compounds to be loaded in the intermediate layer,    -   (c) dry powder mixing the grounded polymer with the active        compound to be loaded in the core;    -   (d) blend extruding the resulting powder mixtures of steps (b)        and (c);    -   (e) cutting the resulting loaded polymer strands into granules,        thereby obtaining a core granulate and an intermediate layer        granulate;    -   (f) lubricating both core granulate and intermediate granulate        with a lubricant;    -   wherein steps (b) and (c) are interexchangeable.

The present invention is further described in the following exampleswhich are not in any way intended to limit the scope of the invention asclaimed.

EXAMPLES Example 1 Preparation of the Three-Layered Ring

Eight (8) three-layer fibres were prepared (A1-A4 and B1-B4). The fibreswere stretched to 3.5 mm (Bx) and 4.0 mm (Ax) from a single capillary(4.1 mm).

In order to mix the active ingredients etonogestrel (steroid A) andethinyl estradiol (steroid B) homogeneously through the polymer, twosubsequent mixing steps were performed. In the fir step, dry powdermixing was performed with the micronized active compounds and polymerpowder. These micronized compounds were mixed with polymer powder in astainless steel drum using a Rhönrad (Barrel-hoop principle) with afixed rotation speed of approximately 26 rpm for 60 minutes. This firstpowder mixing step was performed to mix polymer and active compounds forboth the core (polymer powder and micronized ethinyl estradiol) as wellas for the intermediate layer (polymer powder, micronized ethinylestradiol and micronized etonogestrel). Subsequently the homogenizedpowder mixture was blend extruded using a 25 mm co-rotating double screwblend extruder (Berztorff ZR25) and the resulting medicated polymerstrands were cut into granules using an Scheer granulator. According tothis process a batch core granulate and a batch intermediate layergranulate were manufactured After granulation these batches werelubricated with magnesium stearate in order to facilitate the nextprocessing step (co-extrusion). The composition of the granulate batchesthat was used to manufacture the tri-layer fibre, using a co-extrusionprocess, are described in Table 1 below. TABLE 1 Composition MaterialCore granulate Intermediate layer granulate Etonogestrel —  10.3%Ethinyl estradiol 0.095% 0.092% Evatane 28-25  99.8%  89.5% MagnesiumStearate  0.1%  0.1% Total 100.0% 100.0%

Tri-Layer Co-Extrusion

A Plastic Machinenbau co-extruder (15/18 mm) in combination with anEX10, Fourné (10 mm) extruder was used for trico-extrusion. The 18 mmand the 15 mm Plastic Machinenbau extruders processed the core and theintermediate layer respectively and the 10 mm Fourné extruder was usedto process the skin (outer layer). The three extruders were connectedwith a 3-compartment spinning block (Ankutec, Germany) with 3 separatespinning pumps (to control the volume flow rate (melt flow) of eachlayer). The three melt flows were combined in a spinneret resulting in afibre with 3 layers. A capillary of 4.1 mm was used. All fibres wereextruded at an extrusion temperature of 110° C.

The spinnig rate was tuned to obtain the desired fibre diameter, either3.5 mm or 4.0 mm, and the desired layer thickness for skin andintermediate layer was obtained by adjustment of the spinning pumps.Each of the tri-layer fibre variants was produced by using theappropriate spinning rate and spinning pump settings (totally 2×4variants, A1-A4 and B1-B4). After approximately 20 minutes tri-layerco-extrusion of each variant, the tri-layer fibre was collected on astainless steel reel for 30 minutes. The outer diameter of the fibre wasmeasured on-line continuously using a laser micrometer and recorded. Atthe start and at the end of these 30 minutes, the diameter of the fibre,thickness of the middle layer, thickness of the skin was measured andrecorded.

The loaded fibres were processed at an extrusion speed of 3 m/min forvariants A and 3.9 m/min for variants B. Except variant 3 which wasprocessed at 1.0 m/min for the fibre A3 and 1.3 m/min for the fibre B3.

Fibre Dimensions

The fibre dimensions (outer diameter, intermediate layer thickness andskin thickness) were determined directly after processing and on 10assembled rings. The outer diameter was determined by means of laserthickness gauge (Mitutoyo). The intermediate layer and skin thicknesswere determined using a microscope (Jena). The results for the loadedbatches are shown in Tables 2a and 2b. TABLE 2a Fibre dimensions of 4.0mm loaded fibres processed at an extrusion speed of 3 m/min (exceptvariant A3, which was processed at 1 m/min) Fibre Intermediate diameterlayer Skin Skin Variant [mm] [μm] [μm] polymer R1/R2 R2/R3 A1 4.00 67 66Evatane 1.0341 1.0359 1020 VN3 A2 4.00 61 81 Evatane 1.0422 1.0328 1020VN3 A3 3.99 67 294 Evatane 1.1728 1.0410 1040 VN4 A4 4.00 51 80 Evatane1.0417 1.0273 1020 VN3

TABLE 2b Fibre dimensions of 3.5 mm loaded fibres processed at anextrusion speed of 3.9 m/min (except variant B3, which was processed at1.3 m/min) Fibre Intermediate diameter layer Skin Skin variant [mm] [μm][μm] polymer R1/R2 R2/R3 B1 3.49 54 58 Evatane 1.0344 1.0331 1020 VN3 B23.51 52 73 Evatane 1.0434 1.0319 1020 VN3 B3 3.50 59 261 Evatane 1.17531.0413 1040 VN4 B4 3.50 48 70 Evatane 1.0417 1.0294 1020 VN3

The concentration of the active constituents in core and intermediatelayer was identical for all rings (10.3% ENG, 0.092% EE in intermediatelayer and 0.095 % EE in core). The concentration of 0.092 and 0.095% forthe intermediate layer and core respectively, was considered(practically) identical.

In-vitro Release Rates

Results for in-vitro release are shown in Table 3, FIGS. 1 to 4 andFIGS. 6 to 13. FIGS. 1 and 2 show the release rate of etonogestrel fromone sample of each kind of ring tested. FIGS. 3 and 4 show the releaserate of ethinyl estradiol from one sample of each kind of ring testedFIGS. 6 to 13 also show release rates of etonogestrel and ethinylestradiol from one sample of each kid of ring tested (A1-A4 and B1-B4).In Table 3, the release rates are calculated from six (6) samples ofeach kind of ring tested. TABLE 3 In vitro release rates for allproduced batches at t = 0. In-vitro release rate of In-vitro releaserate etonogestrel (μg/day/ring) of EE (μg/day/ring) Average day RsdAverage day Rsd Batch Day 1 (2-21) (%) Day 21 Day 1 (2-21) (%) Day 21 A1258-264 194 1 177-180 22-22 14 1 11-12 A2 216-225 162 1 149-152 19-20 121 10-10 A3 179-184 119 0 113-114 25-25 11 0 8-9 A4 213-221 156 1 130-13219-20 12 1 10-10 B1 223-232 188 1 157-163 19-21 13 2 10-11 B2 191-197158 1 139-143 18-19 11 1  9-10 B3 168-172 117 1 110-112 26-26 10 1 8-8B4 182-196 145 2 104-111 17-19 11 2 9-9

The day 1 and day 21 release rate is presented as the range of theindividual results of 6 rings (minimum and maximum value are given).

The average day 2-21 release represents the average release rate overthe day 2 up to and including day 21. The presented value is the mean of6 rings.

Assembly

The 4 mm batches (Ax) were cut to pieces of 157 mm and welded with awelding temperature of 130° C. and a welding time of 15 second, on theTWI mono welding unit.

The 3.5 mm fibres were cut into pieces of 157 mm and the ends were gluedtogether (Loctite, type 406 and 770; cat nr. 40621 and 77012).

Thus, a novel three layered ring design, with layers varying from 50 to300 μm, was processed with limited variations in skin thickness andintermediate layer thickness.

Example 2 Physical Stability

The storage stability of NuvaRing® at normal storage temperature (up to30° C.) is limited due to the formation of steroid crystals on thesurface of the skin of the vaginal ring, which leads to an increasedon-set release, the so-called burst release and thus to a decreasedphysical stability. The burst release (day 1 release) of 8 batches of aring of the subject invention was tested at time zero and after 12, 18and 24 months storage at 30° C./75% R.H. in a closed aluminum foillaminate sachet (WO 99/30976). The burst release of 3 representativeNuvaRing® batches was also tested at time zero and after 12, 18 and 24months storage at 30° C./75% R.H. in said closed aluminum foil laminatesachet. The release rate at time zero was determined by analyzing 12rings per batch and the release rate after 12, 18 and 24 months wasdetermined by analyzing 6 rings per batch. The results of these analysesare described in Tables 4, 5 and 6. It is apparent that the burstrelease of all three NuvaRing® batches increases upon storage alreadyafter 12 months at 30° C. With exception of variant A3, all sevenbatches of a ring of the subject invention show a constant or a lowerburst release after storage at 30° C. Visual examination of rings frombatch A3, revealed that the increase of the burst release is not due tothe formation of steroid crystals on the surface of the ring. The factthat the increase of the burst release of batch A3 is not due to crystalformation on the ring surface is also shown by the small differencesobserved between individual test result as indicated by the low RSD(relative standard deviation) value. TABLE 4 day 1 release rate at timezero and after 12 months storage at 30° C./75% R.H. On-Set releaseIndividual results Individual results RSD t = 0 RSD (%) t = 12 months(%) NuvaRing ® N1 186.4, 193.2, 186.6, 185.5, 1.3 210.6, 191.0, 8.3189.9, 188.5, 187.8, 187.6, 179.5, 178.6, 189.6, 184.4, 188.3, 190.2171.8, 205.9 N2 197.4, 199.0, 199.3, 198.2, 1.0 188.5, 190.5, 4.9 199.7,198.3, 205.1, 200.5, 194.4, 195.4, 200.4, 200.1, 200.3, 198.3 215.3,200.1 N3 194.6, 197.5, 197.0, 193.8 2.4 255.1, 325.3, 36.6 198.3, 197.5,198.3, 199.4, 276.3, 215.0 198.7, 204.5, 211.6, 201.8 505.9, 222.5 Ringof the subject invention A1 260.7, 264.9, 263.7, 260.3, 0.9 210.2,207.1, 2.5 263.6, 261.6, 265.2, 264.7, 220.7, 217.2, 263.7, 261.7,265.5, 258.4 209.3, 209.2 A2 219.5, 221.6, 219.5, 219.2, 1.1 184.2,181.1, 1.6 219.4, 225.0, 222.5, 221.7, 176.9, 179.9, 215.8, 223.6,218.0, 221.2 177.3, 177.0 A3 181.0, 180.8, 180.0, 182.2, 0.6 198.7,194.0, 1.4 179.3, 180.7, 180.5, 181.5, 197.7, 202.5, 181.2, 182.1,180.7, 193.6 199.0, 199.5 A4 217.9, 213.4, 216.3, 216.9, 1.1 169.1,171.1, 2.0 215.1, 219.2, 220.1, 220.6, 176.6, 176.6, 221.1, 218.0,217.9, 219.2, 175.0, 169.3 B1 222.9, 230.0, 225.5, 227.8, 1.2 181.6,178.4, 0.9 230.5, 229.4, 229.5, 226.8, 180.8, 181.8, 226.4, 231.9,232.3, 226.6 178.1, 179.0 B2 194.8, 194.5, 194.3, 197.4, 0.9 154.1,152.5, 0.8 190.9, 195.2, 194.9, 192.8, 151.0, 154.3, 191.5, 192.6,194.2, 194.0, 154.1, 153.7 B3 171.3, 171.3, 170.1, 171.4, 0.9 179.0,177.8, 1.2 168.8, 172.0, 171.5, 171.5, 176.6, 183.2, 169.7, 169.7,167.5, 167.9 179.1, 178.9 B4 188.2, 189.9, 195.8, 185.9, 2.3 155.1,150.6, 1.6 189.9, 181.7, 194.3, 192.2, 148.8, 150.4, 191.5, 182.5,189.7, 193.6 151.6, 148.3

TABLE 5 day 1 release rate at time zero and after 18 months storage at30° C./75% R.H. On-Set release Individual results Individual results RSDt = 0 RSD (%) t = 18 months (%) NuvaRing ® N1 186.4, 193.2, 186.6,185.5, 1.3 188.6, 237.0, 18.5 189.9, 188.5, 187.8, 187.6, 301.8, 252.6,189.6, 184.4, 188.3, 190.2 234.0, 186.4 N2 197.4, 199.0, 199.3, 198.2,1.0 210.8, 183.0, 13.7 199.7, 198.3, 205.1, 200.5, 261.6, 202.1, 200.4,200.1, 200.3, 198.3 241.8, 249.4 N3 194.6, 197.5, 197.0, 193.8 2.4479.6, 560.2, 8.6 198.3, 197.5, 198.3, 199.4, 510.2, 483.0, 198.7,204.5, 211.6, 201.8 579.4, 477.9 Ring of the subject invention A1 260.7,264.9, 263.7, 260.3, 0.9 205.5, 209.1, 2.2 263.6, 261.6, 265.2, 264.7,201.9, 207.5, 263.7, 261.7, 265.5, 258.4 199.0, 198.3 A2 219.5, 221.6,219.5, 219.2, 1.1 172.5, 174.0, 1.7 219.4, 225.0, 222.5, 221.7, 174.0,180.5, 215.8, 223.6, 218.0, 221.2 177.0, 174.5 A3 181.0, 180.8, 180.0,182.2, 0.6 194.0, 203.4, 2.5 179.3, 180.7, 180.5, 181.5, 197.9, 201.5,181.2, 182.1, 180.7, 193.6 190.2, 197.9 A4 217.9, 213.4, 216.3, 216.9,1.1 166.9, 163.2, 1.9 215.1, 219.2, 220.1, 220.6, 165.7, 168.1, 221.1,218.0, 217.9, 219.2, 159.4, 166.4 B1 222.9, 230.0, 225.5, 227.8, 1.2171.8, 169.7, 1.3 230.5, 229.4, 229.5, 226.8, 167.6, 173.7, 226.4,231.9, 232.3, 226.6 171.6, 169.4 B2 194.8, 194.5, 194.3, 197.4, 0.9147.6, 146.1, 1.3 190.9, 195.2, 194.9, 192.8, 146.0, 146.8, 191.5,192.6, 194.2, 194.0, 142.9, 143.7 B3 171.3, 171.3, 170.1, 171.4, 0.9172.3, 170.9, 1.5 168.8, 172.0, 171.5, 171.5, 171.7, 172.0, 169.7,169.7, 167.5, 167.9 169.5, 177.1 B4 188.2, 189.9, 195.8, 185.9, 2.3147.5, 146.5, 5.4 189.9, 181.7, 194.3, 192.2, 142.4, 127.3, 191.5,182.5, 189.7, 193.6 145.6, 145.5

TABLE 6 day 1 release rate at time zero and after 24 months storage at30° C./75% R.H. On-Set release Individual results Individual results RSDt = 0 RSD (%) t = 24 months (%) NuvaRing ® N1 186.4, 193.2, 186.6,185.5, 1.3 199.0, 175.9, 8.2 189.9, 188.5, 187.8, 187.6, 219.9, 188.9,189.6, 184.4, 188.3, 190.2 206.9, 184.8 N2 197.4, 199.0, 199.3, 198.2,1.0 247.0, 275.7, 19.0 199.7, 198.3, 205.1, 200.5, 297.3, 371.9, 200.4,200.1, 200.3, 198.3 215.6, 269.0 N3 194.6, 197.5, 197.0, 193.8 2.4271.3, 262.2, 23.6 198.3, 197.5, 198.3, 199.4, 268.1, 247.2, 198.7,204.5, 211.6, 201.8 436.6, 329.4 Ring of the subject invention A1 260.7,264.9, 263.7, 260.3, 0.9 206.4, 208.6, 2.1 263.6, 261.6, 265.2, 264.7,201.8, 203.7, 263.7, 261.7, 265.5, 258.4 209.9, 213.7 A2 219.5, 221.6,219.5, 219.2, 1.1 179.1, 172.1, 2.0 219.4, 225.0, 222.5, 221.7, 173.4,179.8, 215.8, 223.6, 218.0, 221.2 179.8, 172.8 A3 181.0, 180.8, 180.0,182.2, 0.6 197.7, 195.8, 1.6 179.3, 180.7, 180.5, 181.5, 196.8, 197.8,181.2, 182.1, 180.7, 193.6 197.7, 204.9 A4 217.9, 213.4, 216.3, 216.9,1.1 170.1, 163.6, 1.6 215.1, 219.2, 220.1, 220.6, 163.5, 168.2, 221.1,218.0, 217.9, 219.2, 164.6, 166.9 B1 222.9, 230.0, 225.5, 227.8, 1.2171.3, 170.3, 1.5 230.5, 229.4, 229.5, 226.8, 172.1, 175.9, 226.4,231.9, 232.3, 226.6 168.2, 171.8 B2 194.8, 194.5, 194.3, 197.4, 0.9143.5, 145.8, 1.6 190.9, 195.2, 194.9, 192.8, 146.8, 148.0, 191.5,192.6, 194.2, 194.0, 150.0, 148.8 B3 171.3, 171.3, 170.1, 171.4, 0.9173.9, 173.0, 0.9 168.8, 172.0, 171.5, 171.5, 173.9, 177.4, 169.7,169.7, 167.5, 167.9 175.4, 175.9 B4 188.2, 189.9, 195.8, 185.9, 2.3145.0, 145.6, 0.8 189.9, 181.7, 194.3, 192.2, 144.9, 143.9, 191.5,182.5, 189.7, 193.6 142.6, 143.4

Example 3 Improved Three-Layered Ring Versus Ring Described in U.S. Pat.No. 4,292,965

This example illustrates the benefits of the subject improvedthree-layered ring relative to the three-layered ring described in U.S.Pat. No. 4,292,965.

In U.S. Pat. No. 4,292,965 two steroids are accommodated in theintermediate layer, no steroid is present in the core.

The essence of the improved three-layer ring is that the release rate oftwo or more steroids can be adjusted independently from one another andthat the ring is able to sustain this release rate for a more prolongedperiod of time while maintaining physical stability at room temperatureconditions. This example demonstrates the advantage of the improvedthree-layered ring which also has a loaded core over a ring design witha non-medicated core as described in U.S. Pat. No. 4,292,965.

It is not possible to load more than one steroid in the intermediatelayer in the crystalline form and have independent release. In order toadjust the release rate of two (or more) steroids from one compartment,only one steroid can be present in the crystalline phase and theother(s) has to be present in the dissolved phase. In case steroid A ispartly present in the crystalline phase, the steroid in the crystallinelattice will be in dynamic equilibrium with dissolved steroid. Since theconcentration of steroid A is preened, the release rate of steroid A canbe adjusted by choosing the right skin thickness. Considering the factthat the skin thickness is already used as a means to adjust the releaserate of steroid A, the release rate of the second component, steroid Bcan only be tuned by choosing the appropriate concentration. Sincesteroid B is only present in the dissolved form, more steroid can beincorporated into the ring (while maintaining the same concentrationgradient over the membrane) by increasing the volume of the reservoir(the core). Thus, the volume of the reservoir determines the amount ofdissolved steroid B that can be loaded in the ring.

For ring A2 of the subject invention (see example 1) the volume of theintermediate layer and core reservoir can be calculated as follows. Thefibre dimensions of ring A2 are approximately, length 15.7 cm, diameter4.0 mm, thickness intermediate layer about 60 μm and skin about 80 μmand the volume of the intermediate layer and the core of approximatelyV_(int)=0.11 ml and V_(core)=1.71 ml. The densities of both core andintermediate layer are relatively close to 1 ml and consequently themass of the core and intermediate layer are approximately 1.71 g and0.11 g respectively. The concentration EE in the core and intermediatelayer is approximately 0.095% m/m. and hence the core containsapproximately 1620 μg EE and the intermediate layer containsapproximately 106 μg of EE. Thus, in this particular case (A2) more thanapproximately 15 times more EE can be loaded in the improvedthree-layered design compared to a ring with a non-medicated core.

The release of EE from ring A2 as function of time is presented in FIG.3 and can be used to illustrate the advantage of loading the core withEE. The semi-steady state release (release day 2-21) is between 15 and10 μg/day and the content of the intermediate layer alone (106 μg) wouldbe insufficient to sustain a fairly constant release rate over a periodlonger than a few days. After less then 7 days the intermediate layerwould be almost completely depleted and the release rate would dropalready dramatically after a few days.

Moreover, in a ring design such as that of U.S. Pat. No. 4,292,965, dueto internal diffusion into the core, a non-equilibrium situation isobtained and consequently the concentration EE in the intermediate layerwill decrease, which results in a pharmaceutical product with anunstable release profile. However, when the core is loaded with the sameconcentration EE as in the intermediate layer the desired equilibriumsituation is obtained.

This non-steady state behaviour due to internal diffusion (also calledback diffusion) is inherent to the three-layer design according to U.S.Pat. No. 4,292,965 while the improved three layer design eliminates alsothese undesired effects.

Example 4 Preparation of Additional Three-Layered Rings

Twenty (20) additional three-layer fibres were prepared (E-X). The fibrevariants had a dimension of 4 mm (E-V), 3 mm (variant W) and 5 mm(variant X). All fibres were spun from a single capillary (3.6 mm).

Several core and intermediate granulates (C1-C4 and D1-D2 respectively)were prepared using essentially the same method as described in Example1 with the following minor changes:

Granulates C4, D1 and D2 were mixed in a stainless steel drum using aRhonrad (Barrel-hoop principle) with a fixed speed of approximately of47 rpm for 60 minutes. TABLE 7 Composition core granulates EthinylMagnesium Variant Etonogestrel estradiol Ateva 2820A stearate Total C1 —0.16% 99.7% 0.1% 100.0% C2 — 0.13% 99.8% 0.1% 100.0% C3 — 0.20% 99.7%0.1% 100.0% C4 0.33% 0.16% 99.4% 0.1% 100.0%

TABLE 8 Composition intermediate layer granulates Ethinyl MagnesiumVariant Etonogestrel estradiol Ateva 2820A stearate Total D1 10.5% 0.16%89.2% 0.1% 100.0% D2 52.5% 0.16% 47.2% 0.1% 100.0%

Tri-Layer Co-Extrusion

A Fourné trico-extruder (25/18/18 mm) was used for the production of thethree-layered fibres. The 25 mm extruder processed the core layer,whereas the two 18 mm extruders processed the intermediate layer and theskin (outer layer) respectively. The three extruders were connected witha 3-compartment spinning block with 3 separate spinning pumps (tocontrol the volume flow rate (melt flow) of each layer). The three meltflows were combined in a spinneret resulting in a fibre with 3 layers. Acapillary of 3.6 mm was used All fibres were extruded at an extrusiontemperature of 110° C.

The spinning rate was adjusted to obtain the desired fibre diameter of3, 4 or 5 mm. The desired layer thickness for skin and intermediatelayer was obtained by adjustment of the spinning pumps. Each of thetri-layer fibre variants was produced by using the appropriate spinningrate and spinning pump settings (totally 20 variants, E-X). Afterapproximately 20 minutes tri-layer co-extrusion of each variant, thetri-layer fibre was collected on a stainless steel reel for 120 minutes.The outer diameter of the fibre was measured on-line continuously usinga laser micrometer and recorded. At the start and at the end of these120 minutes, the diameter of the fibre, thickness of the middle layer,and the thickness of the skin was measured and recorded. The variants Wand X were collected for only 30 minutes. The loaded fibres wereprocessed at an extrusion speed of 2.00 m/min for variants E-V, at 3.59m/min for variant W, and at 1.28 m/min for variant X.

Fibre Dimensions

The intermediate layer thickness and skin thickness were determined foreach fibre variant from fibre pieces of 4 samples during thetrico-extrusion. The outer diameter was determined for each fibrevariant from fibre pieces of 6 samples during processing ontrico—extruded fibres. The outer diameter was determined by means of alaser thickness gauge (Zumbach). The intermediate layer and skinthickness were determined using a microscope (Jena). The results for theloaded batches are shown in Tables 9a, 9b and 9c. TABLE 9a Fibredimensions of 4 mm loaded fibres processed at an extrusion speed of 2.00m/min Fibre Composition diameter Composition Intermediate intermediateSkin Skin Variant [mm] core layer [μm] layer [μm] R1/R2 R2/R3 polymer E4.01 C1 61 D1 110 1.0580 1.0333 Ateva 1070 F 4.01 C3 60 D1 100 1.05251.0325 Ateva 1070 G 4.02 C3 63 D1 126 1.0669 1.0346 Ateva 1070 H 4.02 C253 D1 94 1.0491 1.0284 Ateva 1070 I 4.04 C2 62 D1 123 1.0648 1.0338Ateva 1070 J 4.02 C1 148 D1 110 1.0579 1.0845 Ateva 1070 K 4.00 C1 28 D2111 1.0588 1.0150 Ateva 1070 L 4.03 C4 67 D1 112 1.0589 1.0365 Ateva1070 M 4.01 C1 61 D1 146 1.0780 1.0339 Ateva 1231 N 4.03 C2 60 D1 1331.0701 1.0329 Ateva 1231 O 4.01 C2 63 D1 167 1.0909 1.0355 Ateva 1231 P4.02 C3 63 D1 132 1.0703 1.0347 Ateva 1231 Q 4.02 C3 60 D1 161 1.08711.0335 Ateva 1231 R 4.04 C1 70 D1 315 1.1848 1.0428 Ateva 1525 S 4.05 C269 D1 277 1.1585 1.0411 Ateva 1525 T 4.02 C2 68 D1 335 1.2000 1.0423Ateva 1525 U 4.04 C3 67 D1 298 1.1731 1.0405 Ateva 1525 V 4.04 C3 65 D1334 1.1981 1.0401 Ateva 1525

TABLE 9b Fibre dimensions of 3 mm loaded fibres processed at anextrusion speed of 3.59 m/min Fibre Composition diameter CompositionIntermediate intermediate Skin Skin Variant [mm] core layer [μm] layer[μm] R1/R2 R2/R3 polymer W 3.03 C1 45 D1 83 1.0580 1.0324 Ateva 1070

TABLE 9c Fibre dimensions of 5 mm loaded fibres processed at anextrusion speed of 1.28 m/min Fibre Composition diameter CompositionIntermediate intermediate Skin Skin Variant [mm] core layer [μm] layer[μm] R1/R2 R2/R3 polymer X 5.00 C1 74 D1 138 1.0584 1.0323 Ateva 1070

In-vitro Release Rates

Results for in-vitro release are shown in Table 10 and FIGS. 14 to 21which show release rates of etonogestrel and ethinyl estradiol of allfibres (E-W). In Table 10 and also in FIGS. 14-21, the release rates arecalculated from six (6) samples of each kind of ring tested. TABLE 10 Invitro release rates for all produced batches at t = 0 In-vitro releaserate of In-vitro release rate etonogestrel (μg/day/ring) of EE(μg/day/ring) Average day Rsd Average day Rsd Batch Day 1 (2-21) (%) Day21 Day 1 (2-21) (%) Day 21 E 140-153 94 1 89-90 23-24 14 3 12-13 F153-162 108 2  99-104 29-30 19 2 17-18 G 125-131 82 1 76-79 24-25 15 212-14 H 148-157 106 2  97-101 20-21 13 3 10-12 I 122-127 82 1 76-7917-18 10 4 8-9 J 208-214 101 1 91-93 23-24 14 2 12-13 K 123-135 95 288-93 21-23 13 3 11-12 L 178-187 98 2 87-91 21-23 13 3 11-11 M 187-197123 1 113-117 34-35 19 2 16-17 N 193-198 133 1 121-125 30-31 17 2 14-15O 165-171 106 1  98-101 26-28 14 2 11-12 P 182-208 138 1 127-131 39-4425 2 22-23 Q 170-180 112 1 103-107 38-40 21 2 19-19 R 186-203 118 1109-113 26-29 19 2 15-17 S 226-236 131 1 123-126 36-38 18 2 14-15 T190-197 110 1 102-105 27-29 15 2 12-12 U 218-224 125 1 116-119 41-44 242 20-22 V 181-193 111 1 103-107 30-32 22 2 19-19 W 120-122 96 1 83-8521-21 13 2 11-12 X 134-144 84 3 77-84 21-22 12 3 10-12

The day 1 and day 21 release rate is presented as the range of theindividual results of 6 rings (minimum and maximum value are given)

The average day 2-21 release represents the average release rate overthe day 2 up to and including day 21. The presented value is the mean of6 rings.

Assembly

The 4 mm fibres (EV) were cut to pieces of 157 mm and welded with awelding temperature of 130° C. and a welding time of 17 seconds, on aCCM (Centrum voor Constructie en Mechatronica, The Netherlands) assemblyunit. Fibres W and X were manually cut to 157 mm and the fibre ends wereglued together using Loctite adhesive (type 406 and 770; cat nr. 40621and 77012).

1. A drug delivery system comprising at least one compartment consistingof (i) a drug-loaded thermoplastic polymer core, (ii) a drug-loadedthermoplastic polymer intermediate layer and (iii) a non-medicatedthermoplastic polymer skin covering the intermediate layer, wherein saidintermediate layer is loaded with (a) crystals of a firstpharmaceutically active compound and with (b) a second pharmaceuticallyactive compound in dissolved form and wherein said core is loaded withsaid second compound in dissolved form.
 2. A drug delivery systemaccording to claim 1 which is physically stable at about 18-30° C.
 3. Adrug delivery system according to claim 1 wherein said second compoundin the core is present in the same concentration as in the intermediatelayer.
 4. A drug delivery system according to claim 1, wherein thedelivery system has a substantially ring-shaped form and is intended forvaginal administration.
 5. A drug delivery system according to claim 1,wherein said first active compound is a steroid and said second activecompound is a steroid.
 6. A drug delivery system according to claim 5,wherein said first active steroid-is a proestrogen.
 7. A drug deliverysystem according to claim 5, wherein said second active steroid is anestrogen.
 8. A drug delivery system according to claim 7, wherein theestrogen is ethinyl estradiol.
 9. A drug delivery system according toclaim 6, wherein the proestrogen is etonogestrel.
 10. A drug deliverysystem according to claim 1, wherein the first active compound isetonogestrel and the second active compound is ethinyl estradiol.
 11. Adrug delivery system according to claim 1, wherein at least the skin butoptionally also the core and the intermediate layer compriseethylene-vinylacetate copolymer as the thermoplastic polymer.
 12. A drugdelivery system according to claim 11, wherein the core and theintermediate layer comprise the same grade of ethylene-vinylacetatecopolymer as the thermoplastic polymer.
 13. A drug delivery systemaccording to claim 11, wherein the core and the intermediate layercomprise a different grade of ethylene-vinylacetate copolymer as thethermoplastic polymer.
 14. A drug delivery system according to claim 1wherein the core is additionally loaded with the first compound.
 15. Adrug delivery system according to claim 8 wherein ethinyl estradiol ispresent in the intermediate layer and in the core at about 0.05-1.5% byweight.
 16. A drug delivery system according to claim 15 wherein ethinylestradiol is present in the intermediate layer and in the core at about0.08-0.5% by weight.
 17. A drug delivery system according to claim 16wherein ethinyl estradiol is present in the intermediate layer and inthe core at about 0.09-0.18% by weight.
 18. A drug delivery systemaccording to claim 17 wherein ethinyl estradiol is present in theintermediate layer and in the core at about 0.09-0.15% by weight.
 19. Adrug delivery system according to claim 16 wherein ethinyl estradiol ispresent in the intermediate layer and in the core at about 0.09-0.20% byweight.
 20. A drug delivery system according to claim 9 whereinetonogestrel is present in the intermediate layer at about 6-80% byweight.
 21. A drug delivery system according to claim 20 whereinetonogestrel is present in the intermediate layer at about 6-70% byweight.
 22. A drug delivery system according to claim 21 whereinetonogestrel is present in the intermediate layer at about 10-53% byweight.
 23. A drug delivery system according to claim 22 whereinetonogestrel is present in the intermediate layer at about 10-30% byweight.
 24. A drug delivery system according to claim 23 whereinetonogestrel is present in the intermediate layer at about 10-15% byweight.
 25. A drug delivery system according to claim 24 whereinetonogestrel is present in the intermediate layer at about 10-12% byweight.
 26. A drug delivery system according to claim 1 wherein theratio R₁/R₂ as described in FIG. 5 is between about 1.0075-2.0000 andthe ratio R₂/R₃ is between about 1.0075-2.0000.
 27. A drug deliverysystem according to claim 26 wherein the ratio R₁/R₂ as described inFIG. 5 is between about 1.0100-1.5000 and the ratio R₂/R₃ is betweenabout 1.0200-1.5000.
 28. A drug delivery system according to claim 27wherein the ratio R₁/R₂ as described in FIG. 5 is between about1.0300-1.3000 and the ratio R₂/R₃ is between about 1.0200-1.5000.
 29. Adrug delivery system according to claim 28 wherein the-ratio R₁/R₂ asdescribed in FIG. 5 is between about 1.0400-1.1800 and the ratio R₂/R₃is between about 1.0200-1.0500.
 30. A drug delivery system according toclaim 1 wherein the ratio R₁/R₂ as described in FIG. 5 is between about1.0300-1.2000 and the ratio R₂/R₃ is between about 1.0100-1.0900.
 31. Adrug delivery system according to claim 5 wherein the intermediate layeradditionally contains an anti-microbial agent.
 32. A drug deliverysystem according to claim 5 wherein the core additionally contains ananti-microbial agent.
 33. A drug delivery system according to claim 1wherein the device contains two compartments.
 34. A drug delivery systemaccording to claim 33 wherein the second compartment contains ananti-microbial agent.
 35. A drug delivery system according to whereinthe anti-microbial agent is mandelic acid condensation polymer.
 36. Amethod of contraception which comprises the steps of (i) positioning thedrug delivery system of claim 1 within the female vaginal tract and (ii)retaining the system within the vaginal tract for at least about 21days.
 37. A method of contraception which comprises the steps of (i)positioning the drug delivery system of claim 1 within the femalevaginal tract (ii) retaining the system within the vaginal tract for atleast about 21 days and (iii) removing the system for an approximate oneweek period to permit menstruation.
 38. A method of concomitantlyproviding contraception and treating or preventing a sexuallytransmitted disease which comprises the steps of (i) positioning thedrug delivery system of claim 31 within the female vaginal tract and(ii) retaining the system within the vaginal tract for at least about 21days.
 39. A method of concomitantly providing contraception and treatingor preventing a sexually transmitted disease which comprises the stepsof (i) positioning the drug delivery system of claim 31 within thefemale vaginal tract (ii) retaining the system within the vaginal tractfor at least about 21 days and (iii) removing the system for anapproximate one week period to permit menstruation.
 40. A contraceptivekit comprising a drug delivery system of claim
 1. 41. A medicament forhormone replacement therapy comprising the drug delivery system ofclaim
 1. 42. A use of the drug delivery system of claim 31 whichprovides contraception and treats and/or prevents a sexually transmitteddisease.
 43. The drug delivery system of claim 42 wherein the disease isAIDS.
 44. The drug delivery system of claim 42 wherein the disease isherpes.
 45. The drug delivery system of claim 42 wherein the disease ischlamydia.
 46. The drug delivery system of claim 42 wherein the diseaseis gonorrhoea.
 47. A method of manufacturing the three-layered drugdelivery system of claim 1 comprising: (i) Producing a loadedhomogeneous polymer core granulate and a loaded homogeneous polymerintermediate layer granulate; (ii) Co-extruding the core granulate andthe intermediate layer granulate with a polymer skin granulate to formthe three-layered drug delivery system.
 48. A method according to claim47 wherein step (i) comprises: (a) grounding the polymer; (b) dry powdermixing the grounded polymer with the active compounds to be loaded inthe intermediate layer; (c) dry powder mixing the grounded polymer withthe active compound to be loaded in the core; (d) blend extruding theresulting powder mixtures of steps (b) and (c); (e) cutting theresulting loaded polymer strands into granules, thereby obtaining a coregranulate and an intermediate layer granulate; (f) lubricating both coregranulate and intermediate granulate with a lubricant; wherein steps (b)and (c) are interexchangeable.
 49. A drug delivery system comprising atleast one compartment consisting of (i) a drug-loaded thermoplasticpolymer core, (ii) a drug-loaded thermoplastic polymer intermediatelayer and (iii) a non-medicated thermoplastic polymer skin covering theintermediate layer, wherein said intermediate layer is loaded withcrystals of a first pharmaceutically active compound and wherein saidcore is loaded with a second pharmaceutically active compound indissolved form.